Many metastatic tumors initially spread through lymphatic tissue and eventually form rapidly developing lymphatic tumors. Treatment of lymphatic metastatic tumors remains a great challenge given the limitations of surgical resection and the low effectiveness of radiotherapy and chemotherapy (Zhang, X., Lu, W. “Recent advances in lymphatic targeted drug delivery system”, Cancer Biol. Med., 2014: 247-254).
Therapies for lymphatic targeted therapy may passively or actively target the lymphatic system. An example of passive delivery is intrapleural placement of a gelatin sponge infused with an antitumor agent (Liu, J. et al. “A novel trans-lymphatic drug delivery system: Implantable gelatin sponge impregnated with PLGA—paclitaxel microspheres”, Biomaterials, 2007: 3236-3244; Liu, J. et al. “Translymphatic Chemotherapy by Intrapleural Placement of Gelatin Sponge Containing Biodegradable Paclitaxel Colloids Controls Lymphatic Metastasis in Lung Cancer”, Cancer Res., 2009: 1174-1181). Nano drug delivery carriers that actively target the lymphatic system include liposomes, nanoparticles, macromolecule polymers, polymer micelles, activated carbons, silicon and nano-emulsions (Zhang, X., Lu, W. “Recent advances in lymphatic targeted drug delivery system”, Cancer Biol. Med., 2014: 247-254). LyP-1 conjugated nanocarriers, and hyaluronic acid nanocarriers are specific developments in lymphatic targeting drug delivery systems.
LyP-1 (CGNKRTRGC) is a cyclic nonapeptide that specifically recognizes the p32/gC1q receptor, which is overexpressed in lymphatic tumors (Laakkonen, P. et al. “A tumor-homing peptide with a targeting specificity related to lymphatic vessels”, Nat. Med., 2002: 751-755). Yan et al. conjugated Lyp-1 to liposomes containing doxorubicin and treated lymphatic tumors (Yan, Z. et al. “LyP-1-conjugated doxorubicin-loaded liposomes suppress lymphatic metastasis by inhibiting lymph node metastases and destroying tumor lymphatics”, Nanotech., 2011: 1-8; Yan, Z. et al. “LyP-1-conjugated PEGylated liposomes: A carrier system for targeted therapy of lymphatic metastatic tumor”, J. Control. Release, 2012: 118-125). Luo et al. conjugated Lyp-1 to PEG-PLGA nanoparticles to target lymphatic tumors (Luo, G. et al. “LyP-1-conjugated nanoparticles for targeting drug delivery to lymphatic metastatic tumors”, Pharm. Nanotech., 2010: 150-156).
Hyaluronic acid (HA) is a natural polysaccharide of alternating D-glucuronic acid and N-acetyl D-glucosamine that is distributed into the lymphatic system and is a ligand for the CD44 receptor, which is overexpressed in lymphatic tumors (Cai, S. et al. “Pharmacokinetics and Disposition of a Localized Lymphatic Polymeric Hyaluronan Conjugate of Cisplatin in Rodents”, J. Pharm. Sci., 2010: 2664-2671). Cai et al. complexed cisplatin to native hyaluronic acid and treated lymphatic tumors (Cai, S. et al. “Intralymphatic Chemotherapy Using a Hyaluronan-Cisplatin Conjugate”, J. Surgical. Res., 2008: 247-252; Cohen, M. et al. “A novel intralymphatic nanocarrier delivery system for cisplatin therapy in breast cancer with improved tumor efficacy and lower systemic toxicity in vivo”, Am. J. Surg., 2009: 781-786; Cai, S. et al. “Carrier-based intralymphatic cisplatin chemotherapy for the treatment of metastatic squamous cell carcinoma of the head & neck”, Ther. Delia, 2010: 237-245; Cai, S. et al. “Pharmacokinetics and Disposition of a Localized Lymphatic Polymeric Hyaluronan Conjugate of Cisplatin in Rodents”, J. Pharm. Sci., 2010: 2664-2671; Forrest, L. et al. Intralymphatic Chemotherapy Drug Carriers, U.S. Pat. No. 8,088,412 B2, Jan. 3, 2012). In an alternative application of hyaluronic acid that does not target the lymphatic system, Hahn et al. treated non-lymphatic tumors with a doxorubicin or epirubicin loaded micelle of an anti-Flt1 peptide (GNQWFI, KGNQWFI or GGNQWFI) conjugated to native hyaluronic acid, where the anti-Flt1 peptide targeted VEGF (Hahn, S. et al. Drug Delivery System Using Hyaluronic Acid-Peptide Conjugate, U.S. Pat. No. 8,895,069 B2, Nov. 25, 2014).